glizidm2

June 2005 q Vol. 58 No. 6 The Indian Practitioner q 1

Original Article

KEY WORDS

Glizid-M, Gliclazide, Metformin, type 2diabetes and diabetes mellitus.

INTRODUCTION

Type 2 or non insulin dependent diabetesmellitus (NIDDM) is a disabling metabolicdisorder that affects more than 150 millionpeople world-wide.1 Three majorpathophysiologic abnormalities areassociated with NIDDM: impaired insulinsecretion, excessive hepatic glucose output,and insulin resistance in skeletal muscle,liver, and adipose tissue.2

An Open Labelled, Prospective, Non-comparative,Multicentric Post Marketing Experience for Evaluationof Efficacy and Safety of Glizid-M In Type 2 Diabetes.Bajpai N*, Singh A P **, Chatterjee A***

*Sr. Executive- Clinical Research, Panacea Biotec Ltd.**Manager- Clinical Research, Panacea Biotec Ltd.***General Manager- Clinical Research, Panacea Biotec Ltd.Correspondence to: Ms. Nidhi Bajpai, Sr. Executive- Clinical Research Panacea Biotec Limited B-1 Extn. /G-3, M.C.I.E. Mathura Road, N.Delhi-44 Email:[email protected]

ABSTRACT

Glizid-M is the fixed dose combination of Gliclazide (80mg) and Metformin (500mg). Theefficacy and safety of this combination therapy in type 2 diabetes has been evaluated in anopen-label, prospective, non-comparative multicentric, phase IV study conducted in India overa period of 6 weeks in accordance with the principles of Good Clinical Practice and theDeclaration of Helsinki. The superiority of the combination therapy and its effects on glycaemicparameters and lipid profile has been observed. A discussion of the same with brief review ofliterature has been presented here. (The Ind. Pract. 2005; 58(6): )

TreatmentThe treatment goals in NIDDM are: The alleviation of symptoms through

normalization of blood glucose levels and,

The prevention of acute and long - termcomplications.3

Although diet and exercise remain thecornerstones of treatment, in the vastmajority of patients with NIDDM,pharmacologic agents are frequently neededto achieve optimal glycaemic control andreduce the incidence of microvascular andpossibly macrovascular complications, as

2 q The Indian Practitioner June 2005 q Vol. 58 No. 6

shown in the United Kingdom ProspectiveDiabetes Study (UKPDS).2

The therapeutic objectives recommendedby the American Diabetes Association (ADA)include fasting plasma glucose (FPG) 80 -120 mg/dL, post prandial plasma glucose< 180 mg/dL, and glycosylated hemoglobin(HbA1c) < 7%

2. For patients with NIDDM, oralmonotherapy may be initially effective forcontrolling blood glucose, but it is associatedwith a high secondary failure rate (primaryfailure is frequent only with patients withhigh baseline blood glucose at the time ofbeginning monotherapy, whereas secondaryfailure is to be expected in the course of thedisease). The different classes of oralhypoglycaemic agents used to treat NIDDMhave complementary mechanisms of action,and their use in combination often results inblood glucose reduction that are significantlygreater than those that can be obtained withmaximal doses of any single drug and thiswas clearly demonstrated in the UKPDS.2, 4

Wide ranges of combinations have been usedeffectively to achieve glycaemic control inpatients in whom oral monotherapy hasfailed4. The best-studied combination is thatof sulfonylurea plus metformin, atherapeutic approach that addresses bothunderlying defects in the disorder: insulindeficiency and insulin resistance.5

SulfonylureasSulfonylureas continue to be used as the

initial pharmacologic therapy, particularlywhen hyperglycemia is pronounced andevidence of impaired insulin secretion ispresent. Furthermore, they are often thefoundation of combination therapy becauseof their ability to increase or maintaininsulin secretion. They have a long history ofuse and few serious side effects (includinghypoglycemia). Placebo - controlled studieshave shown that sulfonylureas reduce FPGlevels by about 54-72 mg/dL and HbA1clevels by 1.5 - 2% in patients with long-standing NIDDM.6-8 Sulfonylureas canincrease insulin secretion at sub stimulatoryconcentrations of glucose, suggesting anenhancement of beta-cell response, andwhen beta cells are exposed to maximallyeffective glucose concentrations,

demonstrating an additive effectindependent of glucose concentrations.9

Prolonged administration of sulfonylureasmay also produce extrapancreatic effectsthat contribute to its hypoglycaemic activity.These effects include reduction of basalhepatic glucose production and an enhancedperipheral sensitivity to insulin secondary tointracellular signaling events that followinsulin receptor binding. Although the maineffect of sulfonylureas appears to bestimulation of basal insulin secretion, theseantidiabetic agents also stimulate thesecretion of insulin throughout the durationof a meal.9

BiguanidesOral biguanide agents (phenformin and

metformin) were introduced for thetreatment of NIDDM in the late 1950s. Theiruse is encouraged for the treatment ofNIDDM either as monotherapy or incombination with sulfonylureas, alpha-glucosidase inhibitors, or insulin. Althoughtheir mechanism of action has not beenclearly determined, decreased hepaticgluconeogenesis is thought to be the primarytherapeutic effect of metformin in NIDDM.In addition, metformin appears to improveutilization of glucose in skeletal muscle andadipose tissue by increasing cell membraneglucose transport. This effect may be due toimproved binding of insulin-to-insulinreceptors since metformin is not effective indiabetics without some residual functioningpancreatic islet cells. Another effect ofmetformin that may contribute to itsglucose-lowering properties is its ability todecrease fatty acid oxidation.10 Othermechanisms may include decreasedintestinal glucose absorption; however, thishas only been observed in animals. Thus, ininsulin-resistant patients with NIDDM,metformin increases insulin sensitivity byboth decreasing hepatic glucose output andenhancing peripheral glucose uptake. In arecent study, 3 months of metformintreatment reversed the increased activity oflymphocyte plasma cell differentiationantigen (PC-I) found in NIDDM.11 Metforminalso decreases plasma very low densitylipoprotein (VLDL) and triglycerides,


resulting in modest decreases in plasmatotal cholesterol.

Rationale of the combination (Gliclazide -Metformin)

The goal of combination therapy is to takeadvantage of the differing mechanisms ofaction of the various pharmacologic agentsand create an individualized treatment planfor achieving effective glycaemic control.

If monotherapy with a sulfonylurea ormetformin fails to achieve the desired level ofglycaemic control, the other second oralagent (if not contraindicated) should beadded, with dose escalation over 4 - 8 weeksto the maximum. The use of a sulfonylureawith metformin is the most widely andextensively studied combination of oralhypoglycaemic agents and lowers HbA1c byan additional 1.7%12. Setter S. M et alreviewed the role of metformin hydrochloridein the treatment of type 2 diabetes mellituswith a focus on dual therapy. At the end ofthe study they concluded that metforminhas multiple benefits in patients with type 2diabetes. It can effectively lower HbA1cvalues, positively affect lipid profiles, andimprove vascular and hemodynamic indices.Adverse effects are generally tolerable andself-limiting. The availability of productscombining metformin with a sulfonylureahas expanded the array of therapies for themanagement of type 2 diabetes.13 There islarge number of literature evidence whichreemphasizes that the high secondaryfailure rates with oral monotherapy and,moreover, the high primary failure rate inpatients with very high blood glucose atdiagnosis, coupled with the effectiveness ofcombination treatment, supports thesuggestion that multiple-drug regimens beconsidered for initial pharmacologictreatment in patients with symptomatic type2 diabetes whose blood glucose is notcontrolled by diet alone.14 With this premisethat treatment a sulfonylurea-metforminthis combination provides a fair to goodglycaemic control, it was also required tocompare this combination with otherexisting choices. A multicentric, double blindstudy conducted by Hanefeld M et alobserved one-year glycaemic control with a

sulfonylurea plus pioglitazone versussulfonylurea plus metformin in patients withtype 2 diabetes, with primary efficacy endpoint of HbA1c at week 52 and also measuredfasting plasma glucose, insulin, and lipidprofiles. The results demonstrated thatHbA1c was reduced by 1.2% in thesulfonylurea plus pioglitazone group and1.36% in the sulfonylurea plus metformingroup; moreover fasting plasma glucose wasreduced by 2.2 and 2.3 mmol/l in therespective groups. Clinically equivalentimprovements in glycaemic control wereobserved for both combinations.15

The current study was planned to furtherestablish the efficacy and safety of Gliclazide Metformin in Indian patients with noninsulin dependent diabetes mellitus.

PATIENTS AND METHODS

Study Objectives and DesignEvaluation of efficacy, safety and

tolerability of fixed dose combination ofGlizid-M type 2 diabetes. An open labeled,non-comparative, and multicentric study.

Study CentersThe study was conducted at 6 centers all

over India.

Study DurationDuration of protocol therapy was 6 weeks.

While the duration of study was 8 months

Study Population and Sample SizeThe study was carried out in patients

suffering from Type 2 diabetes mellitusinadequately controlled by diet, exercise ormetformin or gliclazide alone or anycombination therapy except studymedication. A total of 126 patients wereenrolled in the study and 121 patients wereevaluated at the end of therapy.

Selection of SubjectsInclusion Criteria

Male and female patients with Type 2diabetes, aged 30 to 65 years, body massindex between 20-35 kg/m2, having fastingblood glucose > 126 mg/dL and postprandial blood glucose > 200 mg/dL, havingno serious physical or biochemicalabnormalities other than those generally


associated with type 2 diabetes and whowere willing to give written informed consentwere included in the study.

Exclusion criteriaFollowing patients have been excluded fromthe study:

Patients having diabetes other than noninsulin dependent diabetes mellitus, havinga history of documented oral sulfonylureatreatment failure (primary or secondary),having insulin therapy within the 12 monthsprior the enrolment, having history ofhypersensitivity to sulfonylureas orbiguanides, liver or kidney damage orgastrointestinal disorders, acute infections,diseases of blood or haematopoetic organs,pregnant or lactating women and patientsreceiving any concomitant medication,which may have interacted withhypoglycaemic action of study drug.

Ethical AspectsThe study was conducted in accordance

with the Declaration of Helsinki and ICH-GCP guidelines. Regular monitoring wasdone to ensure compliance with the protocoland ICH-GCP guidelines.

Study ProcedureAfter taking voluntary written informed

consent, subjects were screened forinclusion/exclusion criteria. The pertinentdemographic information and medicalhistory was taken and subjects healthstatus was checked. Subjects who passedthe screening were included in the study andgiven Gliclazide (80mg) and Metformin(500mg) combination 1-2 tablets once ortwice daily with meals up to a maximum of 4tablets per day for 6 weeks. Patients wereassessed on baseline (day 0), week 2, week 4and week 6 of the treatment period. Fastingplasma glucose and 2-hour post prandialplasma glucose was measured on day 0,week 2, week 4 and week 6. Glycosylatedhemoglobin and lipid profile were assessedon day 0 and week 6. Fasting insulin levelwas an optional investigation at baseline(day 0) and week 6.

Subject Compliance Subjects taking .> 70% of test medication

over the duration of therapy were said to be

compliant with the protocol therapy.Subjects taking < 70% of the test medicationover the duration of therapy were said to benon-compliant with protocol therapy.

Concomitant MedicationThe subjects were not allowed to take any

other oral hypoglycaemic agent during thestudy. If any other concomitant drug therapywas administered during the period oftreatment, decision to continue ordiscontinue the subject was based on thepharmacology and pharmacokinetics of thenon-study medications and likelihood ofdrug-drug interactions thereby affecting thepharmacodynamic profile of studymedication.

Criteria For Evaluation Of Study EfficacyAnd SafetyEfficacy Criteria: Primary Endpoints

Reduction in plasma glucose levels(fasting and post prandial glucose)

Reduction in HbA1c level

Secondary Endpoints

Improvement in lipid profile(triglycerides, HDL, LDL & totalcholesterol levels)

Safety Criteria Drug related adverse effects

Vital signs and physical examinations(pulse rate, blood pressure, weight)

Selected biochemistry andhaematology parameters at baselineand after treatment

Serious Adverse Events It was mentioned in the protocol that in

case of a serious ADR, investigator wouldnotify to the sponsor (within 48 hours) andtake appropriate measures to safeguard thesubject. Separate serious adverse eventforms were also provided with each casereport form.

StatisticsDescriptive statistics (minimum,

maximum, mean, median, standarddeviation/ standard error) for continuous


variables and numbers along withpercentage (%) for categorical variables arepresented. Depending upon thedistributional assumptions paired t-test,Wilcoxon signed rank test and paired signtest was employed to compare pre treatmentand post treatment assessment parameters.McNemars test was applied for the paireddesign to detect the differences inpercentages of subjects reporting an adverseeffect symptom.

RESULTS

A total of 126 subjects were enrolled in thestudy and 121 subjects were evaluable at theend of therapy. For statistical analysis, allpatients who complied with > 70% of testmedication consumed over duration ofprotocol therapy were eligible for intent totreat (ITT) analysis.

DemographicsThe study group comprised of both males

and females with the age ranging from 30 to65 years having non-insulin dependentdiabetes (Table 1 & Table 2). The totalnumber of subjects enrolled in the study was126, of which 75 were males and 51 werefemales.

Of these 126 subjects enrolled, 5 subjectsdropped out (because of lost to follow up)which included 2 males and 3 females. Allsubjects were evaluable for body weight &

BMI at baseline and 121 were evaluable atthe end of the study (Week 6). Mean bodyweight & BMI remained almost same at allvisits with negligible variability.

Blood Pressure MonitoringMean systolic blood pressure decreased

continuously from baseline through week 6and mean diastolic blood decreasedmarginally between baseline and week 6. Thedecrease in blood pressure (both systolic &diastolic) was not significant (Table 3).

Efficacy ParametersFasting Blood Glucose Levels

Data for 121 subjects was analyzed forfasting plasma glucose levels at baseline,week 2, week 4 and week 6 of protocoltherapy and the results indicated astatistically significant decrease in fastingplasma glucose levels of 68.2 mg/dL frombaseline to week 6 (Table 4).

Post Prandial Glucose LevelsData for post prandial glucose levels was

analyzed for 121 subjects at baseline andweek 6 and for 120 subjects at week 2 andweek 4 (as one subject did not come forfollow up at week 2 and week 4). The resultsindicated a statistically significant decreasein post prandial plasma glucose levels of98.4 mg/dL from baseline to the end of thetherapy, i.e., week 6 (Table 4).

Table 1Sex distribution of study population

Sex Completed subjects Drop Outs Total

Male 73 (60.3 %) 2 75 (59.5 %)

Female 48 (39.7 %) 3 51 (40.5 %)

Total 121 (100 %) 5 126 (100 %)

Table 2Demographic data (Age, Weight, Height & BMI) category of study population

Parameters(N = 126)

Min Max Mean Median Std. Deviation

Age 30 65 49.6 50.0 8.4

Weight 46.0 90.0 66.4 65.0 8.7

BMI 20.1 34.2 25.0 24.9 3.4


Glycosylated Hemoglobin (HBA1c)Data for HBA1c levels was analyzed for 121

subjects at baseline and week 6 and theresults showed a statistically significantdecrease of 0.28% in the mean value (Table4).

Fasting Insulin level LevelsFasting insulin level being an optional

investigation, data for 68 subjects was

available for analysis at baseline and week 6.Although there was a marginal increase 1.89mIU/ml in the mean value from baseline toweek 6, this change was not statisticallysignificant (Table 4).

Lipid Profile121 subjects were evaluated for lipid

profile at baseline and at week 6. All theparameters of lipid profile demonstrated a

Table 3Descriptive Statistics for Systolic and Diastolic Blood Pressure

Parameters Mean SD Mean SD (p value)

Baseline (N = 126) Week 2 (N = 126) Week 4 (N = 123) Week 6 (N = 121)

B.P. (Systolic) 133.7 12.7 133.2 12.9 132.2 10.3 131.3 10.0(0.295) (0.153) (0.198)

B.P. (Diastolic) 84.3 8.7 84.5 6.8 83.8 6.4 83.4 5.5(1.000) (0.166) (0.143)

Table 4Efficacy Parameters

Parameters Baseline Week 2 Week 4 Week6

N Mean SD N Mean SD N Mean SD N Mean SD

Fasting glucose 121 179.6 41.8 121 145.5 28.3 121 128.4 22.1 121 111.4 19.2

mg/dL

PP glucosemg/dL 121 256.1 52.3 120 200.5 42.1*** 120 178.8 33.5*** 121 157.7 32.2**

GlycosylatedHb (%) 121 8.26 1.31 - - - - 121 7.98 1.27#

Fasting Insulinlevel mIU/ml) 68 96.3 29.3 - - - - 68 98.19 27.99***

Total cholesterol(mg/dL) 121 202.8 34.1 - - - - 121 189.25 28.78

Triglycerides(mg/dL) 121 365.0 54.9 - - - - 121 148.91 42.86

HDL-C (mg/dL) 121 46.3 8.3 - - - - 121 48.14 8.41**

LDL-C (mg/dL) 121 112.5 31.3 - - - - 121 102.56 26.95

*p< 0.05 vs. baseline (Paired t test) - Significant; **p < 0.01 vs. baseline (Paired t test) HighlySignificant; ***p >0.05 vs baseline (Paired t test)- Non Significantp< 0.05 vs. baseline (Paired sign test)- Significant; p> 0.05 vs. baseline (Paired sign test)- NonSignificant#p< 0.05 vs. baseline (Wilcoxon signed rank test)- Significant ##p >0.05 vs. baseline (Wilcoxon signed rank test)- Non Significant


significant change. Decrease of 13.55 mg/dLin mean values of total cholesterol wasobserved, from baseline to week 6. Similarfinding was observed for LDL- cholesterol,which decreased by 9.94 mg/dL frombaseline to week 6. Moreover, triglyceridelevels showed a decrease of 216.09 mg/dL inthe mean values. HDL- cholesterol levelsshowed an increase of 1.84 mg/dL frombaseline to week 6 (Table 4).

Safety ParametersHypoglycaemic Episodes

121 subjects were observed forhypoglycaemic episodes at every visit fromweek 1 to week 6.

More than 90% of the subjects did nothave any hypoglycaemic episodes.Occurrence of a single hypoglycaemicepisode was observed on 35 occasions out ofa total of 726 data points (4.8%). Occurrenceof two hypoglycaemic episodes was observedin 12 (1.7%) occasions and that of threeepisodes only on 2 (0.3%) occasions.

None of the hypoglycaemic episode led tohospitalization or hypoglycaemic coma.(Table 5)

Adverse Drug ReactionsSafety evaluation was done for all the

subjects enrolled in the study.

Heartburn, nausea and abdominaldiscomfort were the most common

gastrointestinal adverse effects of these, thefirst two showed a statistically significantreduction by the end of therapy. Otheradverse reactions were mild, transient andnot of clinical significance (Table 6).

DISCUSSION

Diabetes mellitus is a syndromecharacterized by chronic hyperglycemia anddisturbances of carbohydrate, fat, andprotein metabolism associated with absoluteor relative deficiencies in insulin secretionand/or peripheral insulin uptake16. Anestimated 30 million people worldwide haddiabetes in 1985. By 1995, this number hadshot up to 135 million. The latest WHOestimate (for the number of people withdiabetes world-wide in 2000) is 177 million.This will increase to at least 300 million by2025. The number of deaths attributed todiabetes was previously estimated at justover 800,000. However, it has long beenknown that the number of deaths related todiabetes is considerably underestimated. Amore plausible figure is likely to be around 4million deaths per year related to thepresence of the disorder. This is about 9% ofthe global total. Many of these diabetesrelated deaths are from cardiovascularcomplications. For WHO and theInternational Diabetes Federation (IDF),sponsors of World Diabetes Day, thisincrease can and must be prevented with theright measures.17

Table 5Frequency (%) of Hypoglycemic Episodes (N= 121)

No. Of Total in Total in Total in Total in Total in Total inHypoglycemic Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Episodes

0 112 (92.6%) 112 (92.6%) 114 (94.2%) 117 (96.7%) 111 (91.7%) 111 (91.7%)

1 5 (4.1%) 8 (6.6%) 4 (3.3%) 2 (1.7%) 7 (5.8%) 9 (7.4%)

2 4 (3.3%) 1 (0.8%) 3 (2.5%) 1 (0.8%) 2 (1.7%) 1 (0.8%)

3 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.8%) 1 (0.8%) 0 (0.0%)

Total no.of observed

HypoglycemicEpisodes 13(10.7%) 10 (8.3%) 10 (8.3%) 7 (5.8%) 14 (11.6%) 11 (9.1%)


Table 6Frequency (%) of Adverse Drug Reactions

ADR Specific ComponentNumber of subjects (%)

Week 2 Week 4 Week 6 p value* p value**

Gastrointestinal Heartburn 20(16.1%) 9 (7.3%) 3 (2.4%) 0.003 0.000

Nausea 18(14.5%) 6 (4.8%) 2 (1.6%) 0.008 0.000

Abdominaldiscomfort 18(14.5%) 17(13.7%) 9 (7.3%) 1 0.096

Constipation 13(10.5%) 11 (8.9%) 9 (7.3%) 0.774 0.424

Loss of appetite 12 (9.8%) 17(13.7%) 14(11.4%) 0.267 0.804

Diarrhea 10 (8.1%) 5 (4%) 6 (4.9%) 0.180 0.289

Metallic taste 9 (7.3%) 14(11.3%) 4 (3.3%) 0.267 0.804

Vomiting 6 (4.8%) 5 (4.0%) 4 (3.3%) 1 0.727

Jaundice 1 (0.8%) 2 (1.6%) 0 (0.0%) 1 1

CNS Headache 12 (9.7%) 8 (6.5%) 3 (2.4%) 0.344 0.012

Dizziness 2 (1.6%) 5 (4.0%) 2 (1.6%) 0.375 1

Blurred vision 2 (1.6%) 1 (0.8%) 1 (0.8%) 1 1

Dermatological Rash 6 (4.8%) 2 (1.6%) 2 (1.6%) 0.289 0.289

Flushing 5 (4.0%) 1 (0.8%) 5 (4.0%) 0.219 1

Pruritis 3 (2.4%) 2 (1.6%) 0 (0.0%) 1 0.250

Erythema 2 (1.6%) 2 (1.6%) 2 (1.6%) 1 1

Urticaria 2 (1.6%) 2 (1.6%) 2 (1.6%) 1 1

Allergic vasculitis 1 (0.8%) 1 (0.8%) 1 (0.8%) 1 1

Photosensitivityreactions 0 (0.0%) 2 (1.6%) 2 (1.6%) 0.5 0.5

Musculoskeletal Joint pain 11 (8.8%) 10 (8.0%) 7 (5.7%) 1 0.219

Back pain 12 (9.6%) 7 (5.6%) 6 (4.9%) 0.125 0.109

Hyperglycemia 6 (4.8%) 3 (2.4%) 1 (0.8%) 0.453 0.063

Muscle pain 0 (0.0%) 2 (1.6%) 0 (0.0%) 0.5 -

Sinusitis 1 (0.8%) 0 (0.0%) 0 (0.0%) 1 1

Others Oedema 2 (1.6%) 4 (3.2%) 1 (0.8%) 0.625 1

Sinusitis 1 (0.8%) 0 (0.0%) 0 (0.0%) 1 1

*Week 2 vs. Week 4, **Week 2 vs. Week 6; Statistically Significant (p


Four major classes of oral hypoglycaemicagents are available for treatment. They actas follows at major sites of defects in type 2diabetes mellitus: by increasing insulinavailability (secratagogues, i.e.,sulfonylureas and meglitinides), bysuppressing excessive hepatic glucoseoutput (biguanides, viz metformin), byimproving insulin sensitivity(thiazolidinediones viz, rosiglitazone andpioglitazone) and finally by delayinggastrointestinal glucose absorption (-glucosidase inhibitors viz acarbose andmiglitol). As non insulin dependent diabetesmellitus is a progressive disorder, andalthough oral monotherapy is often initiallysuccessful, it is associated with a highsecondary failure rate, which contributes tothe development of long-term diabeticcomplications resulting from persistenthyperglycemia. For patients not takinginsulin, accumulating evidence suggeststhat combination therapy using oralantidiabetic agents with differentmechanisms of action may be highly effectivein achieving and maintaining target bloodglucose levels. Low-dose combinationtherapy may be associated with fewer sideeffects than higher-dose monotherapy andmay achieve similar or better glycaemiccontrol. A therapeutic approach thataddresses both underlying defects indiabetes viz insulin deficiency and insulinresistance, is gliclazide plus metformin.5

Where gliclazide belongs to the sulfonylureagroup of oral hypoglycaemic agents. It israpidly absorbed from the GIT, and ismetabolised in the liver. It appears in theblood within 1-2 hrs and peak level isachieved in 4-6 hrs. The plasma t1/2 is 8-12hrs and its duration of action is 12 hrs. It isindicated for non insulin dependent diabetesmellitus. It stimulates insulin secretion bypancreatic beta cells. In the long-term itreduces hepatic gluconeogenesis, andincreases insulin effects by acting atreceptor or post-receptor sites. Metformin isthe only currently available oralhypoglycaemic agent that actspredominantly by inhibiting hepatic glucoserelease. As patients with non-insulindependent diabetes often have excess

hepatic glucose output, use of metformin iseffective in lowering glycosylated hemoglobin(HbA1c) by 1-2 % when used as monotherapyor in combination with other blood-glucoselowering agents18. It is extensively plasmaprotein bound (more than 90%).

Addition of gliclazide to metformin therapygives an additive glucose-loweringeffect.19,20,21 Similarly, addition of metforminto sulfonylurea therapy gives an additiveresponse, both with respect to glucose-lowering20,21,22 and lipid-lowering20, 24 effects.Hermann et al20 showed that in mostpatients with newly diagnosed type 2diabetes (FPG level, 12.2 to 13.3 mmol /L[220 to 240 mg/dL]), blood glucose levelscould be controlled with combinedsulfonylurea-metformin therapy. Similarfindings were reported in the UKPDS.25,26

In the current study, patients wereadministered a FDC of Gliclazide (80mg) andMetformin (500mg) i.e. Glizid-M, 1-2 tablets,once or twice daily with meals to a maximumof 4 tablets/day as per the patientsglycaemic control. Assessment of fastingplasma glucose (FPG) and 2-hour postprandial gulcose was performed at thebaseline, at week 2, week 4 and at the end ofthe therapy (i.e. at week 6). Other criticalparameters like glycosylated haemoglobin(HbA1c); lipid profile and fasting insulin levelswere also assessed at baseline and at end ofthe therapy.

The results of the study showed astatistically significant decrease in fastingplasma glucose levels at every visit from amean of 179.6 mg/dL at baseline to 145.5mg/dL at week 2, 128.45 mg/dL at week 4and 111.4 mg/dL at week 6. 98 subjects(86.7%) could achieve the current goals fortreatment of type 2 diabetes mellitus in nonpregnant adults laid by American DiabetesAssociation (ADA 2004) of fasting plasmaglucose of < 130 mg/dL at the end of thetherapy. The efficacy of Glizid-M was furtherdemonstrated by analyzing the mean valuesfor post prandial plasma glucose levels. Noneof the subjects at baseline met the ADAcriteria for optimal glycaemic control,whereas at the end of the therapy, 96subjects (79.3%) achieved the goal of optimal

19,20,21


post prandial plasma glucose < 180 mg/dL(ADA 2004).

Glycosylated Hb (HbA1c) levelssignificantly decreased by 3.4% in just 6weeks of therapy indicating a definite trendtowards better glycaemic control. Resultsshowed a decrease in the mean value ofHbA1c from 8.26 % at baseline to 7.98% atweek 6.

Lipid profile was also analyzed in all thesubjects at baseline and week 6 consideringthe fact that Metformin is additionally usefulin treatment of diabetic dyslipidemia(characterized by low HDL, normal/marginally raised LDL & high triglycerides).Results of this study demonstrated asignificant improvement in lipid profile aftertreatment with Glizid-M. Statisticallysignificant increase in HDL (from meanvalues of 46.3 mg/dL to 48.14 mg/dL),decrease in total cholesterol (from meanvalues of 202.8 mg/dL to 189.25 mg/dL),LDL (from mean values of 112.5 mg/dL to102.56 mg/dL) and significant decrease intriglycerides (from mean values of 365 mg/dL to 148.9 mg/dL) were observed.

Considering the fact that optimal lipidlevels for adults with diabetes as per theAmerican Diabetic Association (ADA 2004)include HDL cholesterol levels > 45 mg/dL,LDL Cholesterol < 100 mg/dL andtriglycerides < 200 mg/dL, the results of thecurrent study demonstrated a highlysignificant improvement in HDL - cholesterol(4.7%) and significant decrease intriglycerides (59.2%). This implies that ADAtarget w.r.t HDL-cholesterol was achieved in12 out of 58 subjects (20.7%) and ADA targetw.r.t triglycerides was achieved in 10 out of24 subjects (41.7%). This fact is particularlyimportant in Indian context where low HDLand high triglycerides are especially commonand increased levels of triglycerides is anindependent risk factor for atheroscleroticcardiovascular disease.

As an optional investigation, at baselineand week 6, 68 subjects were also analyzedfor fasting insulin levels and the changesobserved were statistically not significant atthe end of therapy.

Glizid-M was well tolerated by all thesubjects except few suspected episodes ofhypoglycemia but none of these episodes ledto hospitalization. Few subjects alsocomplained of mild gastrointestinal anddermatological adverse effects althoughthese were not statistically significant.

CONCLUSION

The study demonstrates that the fixeddose combination of Gliclazide andMetformin: Glizid-M is an effective and safeagent in treatment of type 2 diabetesmellitus. It not only helps patient to achieveoptimal glycaemic control but also improvesdiabetic dyslipidemia.

ACKNOWLEDGEMENTS

We at Panacea Biotec Ltd, would like to thankall the doctors, listed below, who participated inthis study and submitted back their valuablefeedback about Glizid- M tablets. This studywould not have been possible without theirparticipation.

1. Dr. Raja Babu Panwar, M.D., D.N.B(Cardiology). Prof. and Head, Dept. OfCardiology, Sardar Patel Medical College AndAssociated Group of Hospital, Bikaner,Rajasthan.

2. Dr. M. K. Dagga, M.D. (Medicine). ProfessorDept. Of Medicine, Lok Narayan Jai PrakashHospital (LNJP), N. Delhi.

3. Dr. Manuj Sharma, M.D, D.M.(Endocrinology). Asst. Prof, Department OfMedicine, Hameedia Hospital, Bhopal (M.P.)

4. Dr. Bishav Mohan, M.D, D.M. (Cardiology).Asst. Prof. & Consultant Cardiologist HERODMC, Heart Institute, Ludhiana, Punjab.

5. Dr. Sachin K. Gupta, M. D. (Medicine).Krishna Diabetes Clinic & EducationResearch Center, Bhopal (M.P.)

6. Dr. Jyoti Khanna, M. D. (Medicine).Consultant, Sharma Hospital, Noida (U.P.)

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